• Roberto Queiroga Lautner, Daniel C Villela, Rodrigo A Fraga-Silva, Neiva Silva, Thiago Verano-Braga, Fabiana Costa-Fraga, Joachim Jankowski, Vera Jankowski, Frederico Sousa, Andreia Alzamora, Everton Soares, Claudiane Barbosa, Frank Kjeldsen, Aline Oliveira, Janaina Braga, Silvia Savergnini, Gisele Maia, Antonio Bastos Peluso, Danielle Passos-Silva, Anderson Ferreira, Fabiana Alves, Almir Martins, Mohan Raizada, Renata Paula, Daisy Motta-Santos, Friederike Klempin, Friederike Kemplin, Adriano Pimenta, Natalia Alenina, Ruben Sinisterra, Michael Bader, Maria Jose Campagnole-Santos, and Robson A S Santos.
• Department of Physiology and Biophysics, National Institute of Science and Technology in Nanobiopharmaceutics, UFMG, Minas Gerais, Brazil.
• Circ. Res. 2013 Apr 12; 112 (8): 1104-11.

RationaleThe renin-angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte, and water balance. Here, we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of angiotensin-converting enzyme-2 angiotensin A or directly from angiotensin-(1-7).ObjectiveTo characterize a novel component of the RAS, alamandine.Methods And ResultsUsing mass spectrometry we observed that alamandine circulates in human blood and can be formed from angiotensin-(1-7) in the heart. Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. Binding of alamandine to Mas-related G-protein-coupled receptor, member D is blocked by D-Pro(7)-angiotensin-(1-7), the Mas-related G-protein-coupled receptor, member D ligand β-alanine and PD123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/β-hydroxypropyl cyclodextrin produced a long-term antihypertensive effect in spontaneously hypertensive rats and antifibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or antiproliferative effect in human tumoral cell lines.ConclusionsThe identification of these 2 novel components of the RAS, alamandine and its receptor, provides new insights for the understanding of the physiological and pathophysiological role of the RAS and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders.

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